EP0322692B1 - Heterocyclically substituted alkyl sulfone amides, method for their preparation, and pharmaceutical preparations - Google Patents

Heterocyclically substituted alkyl sulfone amides, method for their preparation, and pharmaceutical preparations Download PDF

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Publication number
EP0322692B1
EP0322692B1 EP88121188A EP88121188A EP0322692B1 EP 0322692 B1 EP0322692 B1 EP 0322692B1 EP 88121188 A EP88121188 A EP 88121188A EP 88121188 A EP88121188 A EP 88121188A EP 0322692 B1 EP0322692 B1 EP 0322692B1
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group
hydrogen
compound
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general formula
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German (de)
French (fr)
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EP0322692A1 (en
Inventor
Walter-Gunar Dr.Rer.Nat. Friebe
Erhard Dr. Reinholz
Liesel Dr.Med. Doerge
Karlheinz Dr.Rer.Nat. Stegmeier
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Roche Diagnostics GmbH
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Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the optically active compounds and racemic mixtures are also a subject of the invention.
  • EP-A 0146 243 describes structurally analogous compounds which are used as lipoxygenase inhibitors.
  • the new compounds of the general formula have valuable pharmacological properties, in particular they have an excellent antagonistic action against thromboxane A 2 and against prostaglandin endo-peroxides. They inhibit platelet aggregation and prevent smooth muscle constriction and bronchoconstriction. They are also valuable remedies for the treatment of pathological changes in kidney function.
  • cardiovascular diseases and asthma and for the prophylaxis of a shock lung. They can also be used for organ transplants and kidney dialysis and are suitable for preventing recurrences in gastric ulcers. Of particular importance is the possibility of favorably influencing or preventing thrombotic processes. They are suitable for the treatment of peripheral arterial occlusive diseases and can be used, for example, against cerebral and ischemic conditions.
  • R 1 ' R 2 , R 3 , R 4 , R 5 or R 8 represent alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or alkanoyl groups, their alkyl constituents can be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl radicals are preferred.
  • Halogen atoms are fluorine, chlorine and bromine.
  • Preferred compounds of the present invention are compounds of formula 1 in which
  • R 1 , R 3 and R 8 are hydrogen
  • R 2 is hydrogen, bromine, chlorine, methyl or methoxy
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen or ethyl
  • X represents oxygen, sulfur or a group NR 8 ,
  • n is an integer 1 or 2 and the sulfonamido radical is in the 5-position of the heterocycle
  • reaction of a compound of the formula II with a compound of the formula III is advantageously carried out in a solvent or solvent mixture such as dichloromethane, ether, tetrahydrofuran, dioxane or benzene, if appropriate in the presence of an acid-binding agent such as sodium carbonate, triethylamine or pyridine, the latter two also being used simultaneously as solvents can serve in the presence of an acid-activating or dehydrating agent such as thionyl chloride or phosphorus pentachloride, but preferably with a reactive derivative of a compound of the formula, for example with its anhydride or halide, preferably at temperatures between 0 and 100 ° C, for example at temperatures between Room temperature and 50 ° C carried out.
  • a solvent or solvent mixture such as dichloromethane, ether, tetrahydrofuran, dioxane or benzene
  • an acid-binding agent such as sodium carbonate, triethylamine or pyridine
  • a reactive radical Y is preferably halogen atoms such as chlorine or bromine or aliphatic or aromatic sulfonyloxy groups such as methanesulfonyloxy or p-toluenesulfonyloxy.
  • reaction of a compound of formula IV with a compound of formula V is advantageously carried out in a solvent such as acetone, ether, benzene, toluene or dimethylformamide at temperatures between -30 and 100 ° C, preferably at room temperature in the presence of a base such as potassium carbonate or sodium hydride or also carried out in an alcohol in the presence of an alkali alcoholate.
  • a solvent such as acetone, ether, benzene, toluene or dimethylformamide
  • R 3 or R s is, for example, a hydrogen atom
  • this can be substituted by an alkanoyl radical by reaction with an alkyl halide, alkyl sulfonate or alkyl sulfate with an alkyl radical, with a carboxylic acid or with an activated carboxylic acid derivative such as anhydride, halide or ester.
  • An alkanoyl residue representing R 3 or R 8 can be replaced by acidic or alkaline hydrolysis or alcoholysis by a hydrogen atom.
  • the conversion of a radical representing R 5 takes place, for example, by saponification, esterification or transesterification.
  • the hydrogenolysis of a bond formed jointly by R 8 and R 7 is advantageously carried out in a solvent such as water, aqueous ethanol, methanol, acetic acid, ethyl acetate, tetrahydrofuran or dimethylformamide with hydrogen or hydrazine in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium Coal through.
  • a solvent such as water, aqueous ethanol, methanol, acetic acid, ethyl acetate, tetrahydrofuran or dimethylformamide
  • a hydrogenation catalyst such as Raney nickel, platinum or palladium Coal through.
  • the oxidation of an alkylthio group representing R 1 or R 2 is preferably carried out in a solvent or solvent mixture such as water, alcohol, aqueous pyridine, acetone, acetic acid, dilute sulfuric acid or trifluoroacetic acid at temperatures between -80 and 100 ° C.
  • a solvent or solvent mixture such as water, alcohol, aqueous pyridine, acetone, acetic acid, dilute sulfuric acid or trifluoroacetic acid at temperatures between -80 and 100 ° C.
  • the oxidation is expediently carried out with one equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C.
  • a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in dichloromethane or chloroform at -20 to 60 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromosuccinimide in Ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or in acetone at 0 up to 20 ° C or with sulfuryl chloride in
  • the oxidation is expediently carried out with two or more equivalents of the oxidizing agent used, for example with the aforementioned reagents at a higher temperature, if desired, up to 100.degree.
  • the conversion of an alkoxy group representing R 1 or R 2 into a hydroxy group is either in the presence of an acid such as hydrobromic acid or hydroiodic acid, a solution of hydrogen bromide in glacial acetic acid or hydrogen chloride in pyridine or in the presence of a Lewis acid such as aluminum trichloride, boron trichloride or boron tribromide in a solvent such as dichloromethane at temperatures between -80 and 100 ° C.
  • an acid such as hydrobromic acid or hydroiodic acid
  • a solution of hydrogen bromide in glacial acetic acid or hydrogen chloride in pyridine or in the presence of a Lewis acid such as aluminum trichloride, boron trichloride or boron tribromide in a solvent such as dichloromethane at temperatures between -80 and 100 ° C.
  • a solvent such as acetone, alcohol, ether, benzene, toluene or dimethylformamide at temperatures between -30 and 100 ° C., preferably at room temperature in the presence of a base such as potassium carbonate, Sodium hydride or an alkali alcoholate an alkylating agent such as alkyl halide, alkyl sulfate or alkyl sulfonate.
  • the compounds of formula 1 in which at least one of the radicals R 3 or R 6 is hydrogen can also be used the corresponding bases are implemented.
  • Mixtures of the acidic compounds with a suitable alkali metal carbonate or bicarbonate are also suitable.
  • the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as e.g. Olive oil, suspended or dissolved.
  • the substances of the general formula can be administered orally and parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions.
  • Such additives are e.g. Tartrate or borate buffers, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
  • Solid carriers are e.g.
  • Preparations suitable for oral administration can optionally contain flavorings and sweeteners.
  • the dosage administered depends on the age, the health and the weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Typically 0.5 to 40 and preferably 1.0 to 20 mg / kg are effective in one or more applications per day to achieve the desired results.
  • the title compound is obtained from 4-chloro-benzenesulfonyl chloride and 5- (2-aminoethyl) -N-hydroxy-indole-2-carboxylic acid ethyl ester.
  • a mixture of 1.2 g of the compound of Example 2a, 50 ml of ethanol and 0.5 g of palladium-carbon is heated to 100 ° C. under a hydrogen pressure of 280 bar for 3 days. Dilute sodium hydroxide solution is added, the mixture is warmed to 50 ° C. for 2 hours, filtered, acidified, filtered and the precipitate is purified by chromatography.
  • the compound of Example 9 can also be obtained in the following way:

Description

Die vorliegende Erfindung betrifft neue Sulfonamide der allgemeinen formel l,

Figure imgb0001
in welcher

  • R1 und R2 gleich oder verschieden sein können und jeweils Wasserstoff, ein Halogenatom, eine C1- bis C8-Alkyl-, C1- bis C6-Alkoxy-, C1- bis Ce-Alkylthio-, C1- bis C8-Alkylsulfinyl-, C1- bis C6-Alkylsulfonyl-, Trifluormethyl-, Hydroxy- oder Cyanogruppe bedeuten,
  • R3 und R8 gleich oder verschieden sein können und jeweils Wasserstoff, eine C1- bis C6 Alkyl-, eine Benzyl- oder eine C1- bis C6-Alkanoylgruppe bedeuten,
  • R4 und R5 gleich oder verschieden sein können und jeweils Wasserstoff oder eine C1- bis C6-Alkylgruppe bedeuten,
  • R6 und R7 jeweils Wasserstoff darstellen oder gemeinsam eine Bindung bilden, X für Sauerstoff, Schwefel, eine Gruppe NOH oder eine Gruppe NR8 steht und n eine ganze Zahl von 1 bis 4 bedeutet, deren physiologisch verträgliche Salze anorganischer oder organischer Basen und Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel.
The present invention relates to new sulfonamides of the general formula I,
Figure imgb0001
 in which
  • R 1 and R 2 can be the same or different and each hydrogen, a halogen atom, a C 1 - to C 8 -alkyl-, C 1 - to C 6 -alkoxy-, C 1 - to Ce-alkylthio-, C 1 - to C 8 alkylsulfinyl, C 1 to C 6 alkylsulfonyl, trifluoromethyl, hydroxy or cyano group,
  • R 3 and R 8 can be the same or different and each represent hydrogen, a C 1 to C 6 alkyl, a benzyl or a C 1 to C 6 alkanoyl group,
  • R 4 and R 5 can be the same or different and each represent hydrogen or a C 1 to C 6 alkyl group,
  • R 6 and R 7 each represent hydrogen or together form a bond, X represents oxygen, sulfur, a group NOH or a group NR 8 and n represents an integer from 1 to 4, their physiologically tolerable salts of inorganic or organic bases and processes for their preparation and medicaments containing these compounds.

Für den Fall, daß die Verbindungen der allgemeinen Formel ein asymmetrisches Kohlenstoffatom entalten, sind auch die optisch aktiven Verbindungen und racemischen Gemische Gegenstand der Erfindung.In the event that the compounds of the general formula contain an asymmetric carbon atom, the optically active compounds and racemic mixtures are also a subject of the invention.

In der EP-A 0146 243 sind struktur analoge verbindungen beschrieben, die als lipoxygenase-inhibitonen verwendung finden.EP-A 0146 243 describes structurally analogous compounds which are used as lipoxygenase inhibitors.

Die neuen Verbindungen der allgemeinen Formel weisen wertvolle pharmakologische Eigenschaften auf, insbesondere zeigen sie eine ausgezeichnete antagonistische Wirkung gegenüber Thromboxan A2 sowie gegen Prostaglandin-endo-peroxide. Sie inhibieren die Aggregation von Blutplättchen und verhindern die Konstriktion der glatten Muskulatur sowie die Bronchokonstriktion. Sie sind außerdem wertvolle Heilmittel zur Behandlung pathologischer Veränderungen der Nierenfunktion.The new compounds of the general formula have valuable pharmacological properties, in particular they have an excellent antagonistic action against thromboxane A 2 and against prostaglandin endo-peroxides. They inhibit platelet aggregation and prevent smooth muscle constriction and bronchoconstriction. They are also valuable remedies for the treatment of pathological changes in kidney function.

Diese Eigenschaften machen sie zu wertvollen Heilmitteln zur Behandlung beispielweise von cardiovaskulären Erkrankungen und von Asthma und zur Prophylaxe einer Schocklunge. Sie können weiterhin verwendet werden bei Organtransplantationen und Nierendialyse und sind geeignet, Rezidive bei Magengeschwüren zu verhindern. Eine besondere Bedeutung liegt in der Möglichkeit, thrombotische Prozesse günstig zu beeinflussen oder zu verhindern. Sie sind zur Behandlung peripherer arterieller Verschlußkrankheiten geeignet und können beispielsweise gegen cerebrale und ischaemische Zustände eingesetzt werden.These properties make them valuable remedies for the treatment of, for example, cardiovascular diseases and asthma and for the prophylaxis of a shock lung. They can also be used for organ transplants and kidney dialysis and are suitable for preventing recurrences in gastric ulcers. Of particular importance is the possibility of favorably influencing or preventing thrombotic processes. They are suitable for the treatment of peripheral arterial occlusive diseases and can be used, for example, against cerebral and ischemic conditions.

Stehen R1' R2, R3, R4, R5 oder R8 für Alkyl-, Alkoxy-, Alkylthio-, Alkylsulfinyl-, Alkylsulfonyl- oder Alkanoylgruppen, so können deren Alkylbestandteile geradkettig oder verzweigt sein. Bevorzugt sind Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, sek.-Butyl-, tert.-Butyl-, Pentyl- und Hexylreste.If R 1 ' R 2 , R 3 , R 4 , R 5 or R 8 represent alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or alkanoyl groups, their alkyl constituents can be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl radicals are preferred.

Als Halogenatome kommen Fluor, Chlor und Brom in Frage.Halogen atoms are fluorine, chlorine and bromine.

Bevorzugte Verbindungen der vorliegenden Erfindung sind Verbindungen der Formel 1, in welcherPreferred compounds of the present invention are compounds of formula 1 in which

Rl, R3 und R8 WasserstoffR 1 , R 3 and R 8 are hydrogen

R2 Wasserstoff, Brom, Chlor, Methyl oder MethoxyR 2 is hydrogen, bromine, chlorine, methyl or methoxy

R4 Wasserstoff oder MethylR 4 is hydrogen or methyl

R5 Wasserstoff oder Ethyl bedeuten,R 5 is hydrogen or ethyl,

R6 und R7 gemeinsam eine Bindung bilden,R 6 and R 7 together form a bond,

X für Sauerstoff, Schwefel oder eine Gruppe NR8 steht,X represents oxygen, sulfur or a group NR 8 ,

n eine ganze Zahl 1 oder 2 bedeutet und der Sulfonamidorest in 5-Stellung des Heterocyclus stehtn is an integer 1 or 2 and the sulfonamido radical is in the 5-position of the heterocycle

Das erfindungsgemäße Verfahren zur Herstellung der Verbindungen der Formel 1 ist dadurch gekennzeichnet, daß man in an sich bekannter Weise entweder

  • a) eine Verbindung der allgemeinen Formel II
    Figure imgb0002
    in welcher R1 und R2 die obengenannte Bedeutung haben, oder einem reaktiven Derivat hiervon, mit einer Verbindung der allgemeinen Formel 111
    Figure imgb0003
    in welcher R3, R4, R5, R6. R7, X und n die obengenannte Bedeutung haben, oder
  • b) eine Verbindung der allgemeinen Formel IV
    Figure imgb0004
    in welcher Rl, R2 und R3 die obengenannte Bedeutung haben, mit einer Verbindung der allgemeinen Formel V
    Figure imgb0005
    in welcher R4, R5, R6, R7, X und n die obengenannte Bedeutung haben und Y einen reaktiven Rest darstellt, umsetzt, oder
  • c) für den Fall, daß X die Gruppe NH darstellt und R6 und R7 gemeinsam eine Bindung bilden, gemäß einer kombinierten Japp-Klingemann/Fischer-Indol-Synthese eine Verbindung der Formel VI
    Figure imgb0006
    in der Rl, R2, R3 und n die angegebene Bedeutung haben, reduziert, die entstandene Aminogruppe in üblicher Weise in eine Diazoniumgruppe überführt, die Diazoniumgruppe mit 2-Methylacetessigester umsetzt und das entstandene Hydrazon zum Indol cyclisiert, und anschließend gewünschtenfalls einen Rest R3, R5 oder R8 in einen anderen, durch die jeweilige Definition von R3, R6 oder R8 gegebenen Rest umwandelt, eine von R6 und R7 gemeinsam gebildete Bindung durch Hydrogenolyse aufhebt, eine für R1 oder R2 stehende Alkylthiogruppe durch Oxidation in eine Alkylsulfinylgruppe oder Alkylsulfonylgruppe überführt, eine für R1 oder R2 stehende Alkoxygruppe in eine Hydroxygruppe oder eine Hydroxygruppe in eine Alkoxygruppe umwandelt und die erhaltenen Verbindungen der Formel I gewünschtenfalls durch Neutralisation mit nichttoxischen Basen in ihre physiologisch verträglichen Salze umwandelt.
The process according to the invention for the preparation of the compounds of the formula 1 is characterized in that either
  • a) a compound of general formula II
    Figure imgb0002
     in which R 1 and R 2 have the meaning given above, or a reactive derivative thereof, with a compound of the general formula III
    Figure imgb0003
     in which R 3 , R 4 , R 5 , R 6 . R 7 , X and n have the meaning given above, or
  • b) a compound of the general formula IV
    Figure imgb0004
     in which R 1 , R 2 and R 3 have the meaning given above, with a compound of the general formula V
    Figure imgb0005
     in which R 4 , R 5 , R 6 , R 7 , X and n have the meaning given above and Y represents a reactive radical, or
  • c) in the event that X represents the group NH and R 6 and R 7 together form a bond, according to a combined Japp-Klingemann / Fischer indole synthesis, a compound of formula VI
    Figure imgb0006
     in which R 1 , R 2 , R 3 and n have the meaning given, reduced, the amino group formed converted in a conventional manner into a diazonium group, the diazonium group reacted with 2-methyl acetoacetate and the hydrazone formed cyclized to the indole, and then, if desired, a residue Converts R 3 , R 5 or R 8 into another radical given by the respective definition of R 3 , R 6 or R 8 , breaks a bond formed jointly by R 6 and R 7 by hydrogenolysis, one for R 1 or R 2 alkylthio group is converted by oxidation into an alkylsulfinyl group or alkylsulfonyl group, an alkoxy group representing R 1 or R 2 is converted into a hydroxyl group or a hydroxyl group into an alkoxy group and the compounds of formula I obtained, if desired, into their by neutralization with non-toxic bases converts physiologically acceptable salts.

Die Umsetzung einer Verbindung der Formel llmit einer Verbindung der Formel lll wird zweckmäßig in einem Lösungsmittel oder Lösungsmittelgemisch wie Dichlormethan, Ether, Tetrahydrofuran, Dioxan oder Benzol gegebenenfalls in Gegenwart eines säurebindenden Mittels wie Natriumcarbonat, Triethylamin oder Pyridin, wobei die beiden letzteren gleichzeitig auch als Lösungsmittel dienen können, in Gegenwart eines die Säure aktivierenden oder wasserentziehenden Mittels wie Thionylchlorid oder Phosphorpentachlorid, vorzugsweise jedoch mit einem reaktionsfähigen Derivat einer Verbindung der Formell, beispielsweise mit deren Anhydrid oder Halogenid, vorzugsweise bei Temperaturen zwischen 0 und 100°C, zum Beispiel bei Temperaturen zwischen Raumtemperatur und 50°C, durchgeführt.The reaction of a compound of the formula II with a compound of the formula III is advantageously carried out in a solvent or solvent mixture such as dichloromethane, ether, tetrahydrofuran, dioxane or benzene, if appropriate in the presence of an acid-binding agent such as sodium carbonate, triethylamine or pyridine, the latter two also being used simultaneously as solvents can serve in the presence of an acid-activating or dehydrating agent such as thionyl chloride or phosphorus pentachloride, but preferably with a reactive derivative of a compound of the formula, for example with its anhydride or halide, preferably at temperatures between 0 and 100 ° C, for example at temperatures between Room temperature and 50 ° C carried out.

Für einen reaktiven Rest Y stehen vorzugsweise Halogenatome wie Chlor oder Brom oder aliphatische oder aromatische Sulfonyloxygruppen wie beispielsweise Methansulfonyloxy oder p-Toluolsulfonyloxy.A reactive radical Y is preferably halogen atoms such as chlorine or bromine or aliphatic or aromatic sulfonyloxy groups such as methanesulfonyloxy or p-toluenesulfonyloxy.

Die Umsetzung einer Verbindung der Formel IV mit einer Verbindung der Formel V wird zweckmäßig in einem Lösungsmittel wie Aceton, Ether, Benzol, Toluol oder Dimethylformamid bei Temperaturen zwischen -30 und 100°C, vorzugsweise bei Raumtemperatur in Gegenwart einer Base wie Kaliumcarbonat oder Natriumhydrid oder auch in einem Alkohol in Gegenward eines Alkalialkoholats vorgenommen.The reaction of a compound of formula IV with a compound of formula V is advantageously carried out in a solvent such as acetone, ether, benzene, toluene or dimethylformamide at temperatures between -30 and 100 ° C, preferably at room temperature in the presence of a base such as potassium carbonate or sodium hydride or also carried out in an alcohol in the presence of an alkali alcoholate.

Die Verbindungen der Formel lll sind größtenteils neu und können nach literaturbekannten Verfahren aus beschriebenen Vorstufen synthetisiert werden. So werden z.B. Halogenmethyl-Derivate von Benzofuran-, Benzothiophen- bzw. Indol-2-carbonsäure mit Cyaniden zu den entsprechenden Cyanmethylverbindungen umgesetzt, die anschließend zu den Aminoethylderivaten reduziert werden. Verbindungen der Formel lll mit n = 1 werden direkt aus dem Halogenmethyl-Derivaten durch Umsetzung mit R3NH2 erhalten.The compounds of the formula III are largely new and can be synthesized from the precursors described by processes known from the literature. For example, halomethyl derivatives of benzofuran, benzothiophene or indole-2-carboxylic acid are reacted with cyanides to give the corresponding cyanomethyl compounds, which are then reduced to the aminoethyl derivatives. Compounds of formula III with n = 1 are obtained directly from the halomethyl derivatives by reaction with R 3 NH 2 .

Die Halogenmethyl-Derivate der Formel V (n = 1, Y = CI) werden durch Chlormethylierung der entsprechenden Heterocyclen erhalten.The halomethyl derivatives of the formula V (n = 1, Y = CI) are obtained by chloromethylation of the corresponding heterocycles.

Die Umwandlung von Verbindungen der allgemeinen Formel in andere Verbindungen der allgemeinen formel kann nach geläufigen Methoden erfolgen.The conversion of compounds of the general formula into other compounds of the general formula can be carried out using conventional methods.

Steht für R3 oder Rs beispielsweise ein Wasserstoffatom, so kann dieses durch Umsetzung mit einem Alkylhalogenid, Alkylsulfonat oder Alkylsulfat durch einen Alkylrest, mit einer Carbonsäure oder einem aktivierten Carbonsäurederivat wie Anhydrid, Halogenid oder Ester durch einen Alkanoylrest substituiert werden.If R 3 or R s is, for example, a hydrogen atom, this can be substituted by an alkanoyl radical by reaction with an alkyl halide, alkyl sulfonate or alkyl sulfate with an alkyl radical, with a carboxylic acid or with an activated carboxylic acid derivative such as anhydride, halide or ester.

Ein für R3 oder R8 stehender Alkanoylrest kann durch saure oder alkalische Hydrolyse oder Alkoholyse durch ein Wasserstoffatom ersetzt werden.An alkanoyl residue representing R 3 or R 8 can be replaced by acidic or alkaline hydrolysis or alcoholysis by a hydrogen atom.

Die Umwandlung eines für R5 stehenden Restes erfolgt beispeilsweise durch Verseifung, Veresterung oder Umesterung.The conversion of a radical representing R 5 takes place, for example, by saponification, esterification or transesterification.

Die Hydrogenolyse einer durch R8 und R7 gemeinsam gebildeten Bindung führt man zweckmäßig in einem Lösungsmittel wie Wasser, wässriges Ethanol, Methanol, Essigsäure, Essigester, Tetrahydrofuran oder Dimethylformamid mit Wasserstoff oder Hydrazin in Gegenwart eines Hydrierkatalysators wie Raney-Nickel, Platin oder Palladium-Kohle durch.The hydrogenolysis of a bond formed jointly by R 8 and R 7 is advantageously carried out in a solvent such as water, aqueous ethanol, methanol, acetic acid, ethyl acetate, tetrahydrofuran or dimethylformamide with hydrogen or hydrazine in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium Coal through.

Die Oxidation einer für R1 oder R2 stehenden Alkylthiogruppe nimmt man vorzugsweise in einem Lösungsmittel oder Lösungsmittelgemisch wie beispielsweise Wasser, Alkohol, wässriges Pyridin, Aceton, Essigsäure, verdünnte Schwefelsäure oder Trifluoressigsäure bei Temperaturen zwischen -80 und 100°C vor.The oxidation of an alkylthio group representing R 1 or R 2 is preferably carried out in a solvent or solvent mixture such as water, alcohol, aqueous pyridine, acetone, acetic acid, dilute sulfuric acid or trifluoroacetic acid at temperatures between -80 and 100 ° C.

Zur Herstellung einer Alkylsulfinylgruppe wird die Oxidation zweckmäßig mit einem Äquivalent des verwendeten Oxidationsmittels durchgeführt, beispielsweise mit Wasserstoffperoxid in Eisessig, Trifluoressigsäure oder Ameisensäure bei 0 bis 20°C oder in Aceton bei 0 bis 60°C, mit einer Persäure wie Perameisensäure in Eisessig oder Trifluoressigsäure bei 0 bis 50°C oder mit m-Chlorperbenzoesäure in Dichlormethan oder Chloroform bei -20 bis 60°C, mit Natriummetaperiodat in wässrigem Methanol oder Ethanol bei-15 bis 25°C, mit Brom in Eisessig oderwässriger Essigsäure, mit N-Bromsuccinimid in Ethanol, mit tert.-Butylhypochlorit in Methanol bei -80 bis -30°C, mit Jodbenzodichlorid in wässrigem Pyridin bei 0 bis 50°C, mit Salpetersäure in Eisessig bei 0 bis 20°C, mit Chromsäure in Eisessig oder in Aceton bei 0 bis 20°C oder mit Sulfurylchlorid in Dichlormethan bei -70°C ; der hierbei erhaltene Thioether-Chlor-Komplex wird zweckmäßig mit wässrigem Ethanol hydrolysiert.To produce an alkylsulfinyl group, the oxidation is expediently carried out with one equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C. or in acetone at 0 to 60 ° C., with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in dichloromethane or chloroform at -20 to 60 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromosuccinimide in Ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or in acetone at 0 up to 20 ° C or with sulfuryl chloride in dichloromethane at -70 ° C; the thioether-chlorine complex obtained is expediently hydrolyzed with aqueous ethanol.

Zur Herstellung einer Alkylsulfonylgruppe wird die Oxidation zweckmäßig mit zwei oder mehr Aequivalenten des verwendeten Oxidationsmittels durchgeführt, beispielsweise mit den vorgenannten Reagenzien bei gewünschtenfalls höherer Temperatur bis 100°C.To produce an alkylsulfonyl group, the oxidation is expediently carried out with two or more equivalents of the oxidizing agent used, for example with the aforementioned reagents at a higher temperature, if desired, up to 100.degree.

Die Umwandlung einer für R1 oder R2 stehenden Alkoxygruppe in eine Hydroxygruppe wird entweder in Gegenwart einer Säure wie Bromwasserstoffsäure oder lodwasserstoffsäure, einer Lösung von Bromwasserstoff in Eisessig oder Chlorwasserstoff in Pyridin oder in Gegenwart einer Lewissäure wie Aluminiumtrichlorid, Bortrichlorid oder Bortribromid in einem Lösungsmittel wie Dichlormethan bei Temperaturen zwischen -80 und 100°C durchgeführt.The conversion of an alkoxy group representing R 1 or R 2 into a hydroxy group is either in the presence of an acid such as hydrobromic acid or hydroiodic acid, a solution of hydrogen bromide in glacial acetic acid or hydrogen chloride in pyridine or in the presence of a Lewis acid such as aluminum trichloride, boron trichloride or boron tribromide in a solvent such as dichloromethane at temperatures between -80 and 100 ° C.

Für die Alkylierung einer für R1 oder R2 stehenden Hydroxygruppe setzt man vorzugsweise in einem Lösungsmittel wie Aceton, Alkohol, Ether, Benzol, Toluol oder Dimethylformamid bei Temperaturen zwischen -30 und 100°C, vorzugsweise bei Raumtemperatur in Gegenwart einer Base wie Kaliumcarbonat, Natriumhydrid oder einem Alkalialkoholat eine Alkylierungsmittel wie Alkylhalogenid, Alkylsulfat oder Alkylsulfonat ein.For the alkylation of a hydroxyl group representing R 1 or R 2 , preference is given to using a solvent such as acetone, alcohol, ether, benzene, toluene or dimethylformamide at temperatures between -30 and 100 ° C., preferably at room temperature in the presence of a base such as potassium carbonate, Sodium hydride or an alkali alcoholate an alkylating agent such as alkyl halide, alkyl sulfate or alkyl sulfonate.

Zur Herstellung von Salzen mit physiologisch verträglichen organischen oder anorganischen Basen wie beispielsweise Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid, Ammoniumhydroxid, Methylglucamin, Morpholin, Triethylamin oder Ethanolamin können die Verbindungen der Formel 1, in denen mindestens einer der Reste R3 oder R6 Wasserstoff bedeutet, mit den entsprechenden Basen umgesetzt werden. Auch Mischungen der sauren Verbindungen mit einem geeigneten Alkalicarbonat bzw. -hydrogencarbonat kommen in Betracht.For the preparation of salts with physiologically compatible organic or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine, triethylamine or ethanolamine, the compounds of formula 1 in which at least one of the radicals R 3 or R 6 is hydrogen can also be used the corresponding bases are implemented. Mixtures of the acidic compounds with a suitable alkali metal carbonate or bicarbonate are also suitable.

Zur Herstellung von Arzneimitteln werden die Verbindungen der allgemeinen Formel I in an sich bekannter Weise mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder Öl, wie z.B. Olivenöl, suspendiert oder gelöst.For the production of pharmaceuticals, the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as e.g. Olive oil, suspended or dissolved.

Die Substanzen der allgemeinen Formel können in flüssiger oderfester Form oral und parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Stabilisierungsmittel, Lösungsvermittler und/oder Puffer enthält. Derartige Zusätze sind z.B. Tartrat- oder Borat-Puffer, Ethanol, Dimethylsulfoxid, Komplexbildner (wie Ethylendiamintetraessigsäure), hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregulierung oder Polyethylen-Derivate von Sorbitanhydriden. Feste Trägerstoffe sind z.B. Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäure, höhermolekulare Fettsäuren (wie Stearinsäure), Gelatine, Agar-Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette oder feste hochmolekulare Polymere (wie Polyethylenglykole). Für die orale Applikation geeignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe enthalten.The substances of the general formula can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions. Such additives are e.g. Tartrate or borate buffers, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides. Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can optionally contain flavorings and sweeteners.

Die verabreichte Dosierung hängt vom Alter, der Gesundheit und dem Gewicht des Empfängers, dem Ausmaß der Krankheit, der Art gleichzeitiger gegebenenfalls durchgeführter weiterer Behandlungen, der Häufigkeit der Behandlungen und der Art der gewünschten Wirkung ab. Üblicherweise beträgt die tägliche Dosis der aktiven Verbindung 0,1 bis 50 mg/kg Körpergewicht. Normalerweise sind 0,5 bis 40 und vorzugsweise 1,0 bis 20 mg/kg in einer oder mehreren Anwendungen pro Tag wirksam, um die gewünschten Resultate zu erhalten.The dosage administered depends on the age, the health and the weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired. The daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Typically 0.5 to 40 and preferably 1.0 to 20 mg / kg are effective in one or more applications per day to achieve the desired results.

Bevorzugt im Sinne der Erfindung sind außer den in den Beispielen genannten Verbindungen der Formel sowie deren Salzen insbesondere die folgenden :

  • 5-[2-(3-Trifluormethyl-benzolsulfonamido)ethyl]benzo[b] furan-2-carbonsäure
  • 5-[2-(4-Cyan-benzolsulfonamido)ethyl]benzo[b]furan-2-carbonsäure
  • 5-[2-(4-Methylthio-benzolsulfonamido)ethyl]benzo[b]furan-2-carbonsäure
  • 5-[2-(4-Methylsulfinyl-benzolsulfonamido)ethyl]benzo[b] furan-2-carbonsäure
  • 5-(2-(4-Methylsulfonyl-benzolsulfonamido)ethyl]benzo[b] furan-2-carbonsäure
  • 5-(2-(4-Hydroxy-benzolsulfonamido)ethyl]benzo[b]furan-2-carbonsäure
  • 5-[2-(2,4-Dimethyl-benzolsulfonamido)ethyl]benzo[b]furan-2-carbonsäure
  • 5-[2-(N-Benzyl-4-chlor-benzolsulfonamido)ethyl]benzo[b] furan-2-carbonsäure
  • 5-[2-(4-N-Acetyl-4-chlor-benzolsulfonamido)ethyl]benzo[b] furan-2-carbonsäure
  • 5-[3-(4-Chlor benzolsulfonamido)propyl]benzo[bjfuran-2-carbonsäure
  • 5-[4-(4-Chlor benzolsulfonamido)butyl]benzo[bjfuran-2-carbonsäure
  • 5-[2-(4-Chlor-benzolsulfonamido)ethyl]-N-acetyl-Indol-2-carbonsäure
  • 5-[2-(4-Chlor-benzolsulfonamido)ethyl-N-benzoyl-indol-2-carbonsäure
In addition to the compounds of the formula and their salts mentioned in the examples, the following are particularly preferred in the sense of the invention:
  • 5- [2- (3-trifluoromethyl-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [2- (4-cyano-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [2- (4-Methylthio-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [2- (4-Methylsulfinyl-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- (2- (4-Methylsulfonyl-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- (2- (4-Hydroxy-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [2- (2,4-Dimethyl-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [2- (N-Benzyl-4-chloro-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [2- (4-N-Acetyl-4-chloro-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid
  • 5- [3- (4-chlorobenzenesulfonamido) propyl] benzo [bjfuran-2-carboxylic acid
  • 5- [4- (4-chlorobenzenesulfonamido) butyl] benzo [bjfuran-2-carboxylic acid
  • 5- [2- (4-chloro-benzenesulfonamido) ethyl] -N-acetyl-indole-2-carboxylic acid
  • 5- [2- (4-chloro-benzenesulfonamido) ethyl-N-benzoyl-indole-2-carboxylic acid

Beispiel 1example 1 5-[2-(4-Chlorbenzolsulfonamido)ethyl]benzo[b]furan-2-carbonsäureethylester5- [2- (4-Chlorobenzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid ethyl ester

Eine Suspension von 8.1 g (30 mmol) 5-(2-Amino-ethyl)benzo[b]furan-2-carbonsäureethylester-hydrochlorid in 100 ml Dichlormethan versetzt man mit 10.0 g (100 mmol) Triethylamin, kühlt auf 5°C und tropft eine Lösung von 8.4 g (40 mmoi) 4-Chlor-benzolsulfochlorid ein. Man rührt 4 h bei Raumtemperatur nach, engt ein, nimmt in Ethylacetat auf, wäscht neutral, engt ein und chromatographiert an Kieselgel. Elution mit Dichlormethan ergibt 5.5 g Titelverbindung (45% d.Th.) vom Schmp. 123-125°C.A suspension of 8.1 g (30 mmol) of 5- (2-amino-ethyl) benzo [b] furan-2-carboxylic acid ethyl ester hydrochloride in 100 ml of dichloromethane is mixed with 10.0 g (100 mmol) of triethylamine, cooled to 5 ° C. and a solution of 8.4 g (40 mmoi) of 4-chlorobenzenesulfochloride is added dropwise. The mixture is stirred for 4 h at room temperature, concentrated, taken up in ethyl acetate, washed neutral, concentrated and chromatographed on silica gel. Elution with dichloromethane gives 5.5 g of the title compound (45% of theory), mp. 123-125 ° C.

Das Ausgangsmaterial kann wie folgt erhalten werden :

  • Durch Umsetzung von 5-Chlormethyl-benzo[b]furan-2-carbonsäureethylester (Chem. Abstr. 1959, 3185 d) mit überschüssigem Natriumcyanid in Dimethylformamid gelangt man mit 90% Ausbeute zum 5-Cyanomethyl-benzo[b]furan-2-carbonsäureethylester vom Schmp. 74-76°C (aus Ethylacetat), welcher in essigsaurer Lösung über Platinoxid zum 5-(2-Amino-ethyl)benzo[b]furan-2-carbonsäureethylester hydriert wird. Aus dessen ethanolischer Lösung kann mit etherischer Chlorwasserstofflösung das Hydrochlorid vom Schmp. 188-190°C gefällt werden (Ausbeute 64% d.Th.).
The starting material can be obtained as follows:
  • By reaction of 5-chloromethyl-benzo [b] furan-2-carboxylic acid ethyl ester (Chem. Abstr. 1959, 3185 d) with excess sodium cyanide in dimethylformamide, 5-cyanomethyl-benzo [b] furan-2- is obtained in 90% yield. carboxylic acid ethyl ester of melting point 74-76 ° C (from ethyl acetate), which is hydrogenated in acetic acid solution over platinum oxide to give 5- (2-amino-ethyl) benzo [b] furan-2-carboxylic acid ethyl ester. From its ethanolic solution, the hydrochloride of mp. 188-190 ° C can be precipitated with ethereal hydrogen chloride solution (yield 64% of theory).

Beispiel 2Example 2

In analoger Weise wie in Beispiel 1 beschrieben erhält man aus 5-(2-Amino-ethyl)benzo(b]furan-2-car bonsäureethylester-hydrochlorid und den angegebenen Sulfonsäurederivaten :

Figure imgb0007
In an analogous manner to that described in Example 1, ethyl (5-) (2-amino-ethyl) benzo (b] furan-2-caroate hydrochloride and the sulfonic acid derivatives given are obtained:
Figure imgb0007

Beispiel 3Example 3 5-[2-(4-Chlor-benzolsulfonamido)ethyl]benzo[b)thiophen-2-carbonsäureethvlester5- [2- (4-Chloro-benzenesulfonamido) ethyl] benzo [b) thiophene-2-carboxylic acid, ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 5-(2-Aminoethyl)benzo[b]thiophen-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chloro-benzenesulfochloride and 5- (2-aminoethyl) benzo [b] thiophene-2-carboxylic acid ethyl ester.

Beispiel 4Example 4 5-[2-(4-Chlor benzolsulfonamido)ethyl]-3-methyl-benzo[b]furan-2-carbonsäureethylester5- [2- (4-Chlorobenzenesulfonamido) ethyl] -3-methyl-benzo [b] furan-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 5-(2-Aminoethyl)-3-methyl-benzo[b]furan-2-carbonsäureethylester.The title compound is obtained from 4-chlorobenzenesul in an analogous manner to that described in Example 1 fochloride and 5- (2-aminoethyl) -3-methyl-benzo [b] furan-2-carboxylic acid ethyl ester.

Beispiel 5Example 5 5-(4-Chlor-benzolsulfonamido)methyl)benzo[b]furan-2-carbonsäureethylester5- (4-Chloro-benzenesulfonamido) methyl) benzo [b] furan-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 5-Aminomethyl-benzo[b]furan-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chloro-benzenesulfochloride and 5-aminomethyl-benzo [b] furan-2-carboxylic acid ethyl ester.

Beispiel 6Example 6 6-[2-(4-Chlor-benzolsulfonamido)ethyl]benzo-[b]furan-2-carbonsäureethylester6- [2- (4-chloro-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschriben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 6-(2-Aminoethyl)benzo[b]furan-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chloro-benzenesulfochloride and 6- (2-aminoethyl) benzo [b] furan-2-carboxylic acid ethyl ester.

Beispiel 7Example 7 4-[2-Chlor-benzolsulfonamido)ethyl]benzo-[b]furan-2-carbonsäureethylester4- [2-chloro-benzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispeil 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 4-(2-Aminoethyl)benzo[b]furan-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chlorobenzenesulfochloride and 4- (2-aminoethyl) benzo [b] furan-2-carboxylic acid ethyl ester.

Beispiel 8Example 8 5-[2-(4-Chlor benzolsulfonamido)ethyl]-2,3-dihydro-benzo[b]furan-2-carbonsäureethylester5- [2- (4-Chlorobenzenesulfonamido) ethyl] -2,3-dihydro-benzo [b] furan-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 5-(2-Aminoethyl)-2,3-dihydro-benzo[b]furan-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chloro-benzenesulfochloride and 5- (2-aminoethyl) -2,3-dihydro-benzo [b] furan-2-carboxylic acid ethyl ester.

Beispiel 9Example 9 5-[2-(4-Chlor-benzolsulfonamido)ethyl]indol-2-carbonsäureethylester5- [2- (4-Chloro-benzenesulfonamido) ethyl] indole-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 5-(2-Aminoethyl) indol-2-carbonsäureethylester (Ausbeute 34% ; Schmp. 193-195° C, aus Ethanol.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chloro-benzenesulfochloride and 5- (2-aminoethyl) indole-2-carboxylic acid ethyl ester (yield 34%; mp. 193-195 ° C.) from ethanol.

Beispiel 10Example 10 5-[2-(4-Chlor-benzolsulfonamido)ethyl]-N-hydroxy-indol-2-carbonsäureethylester5- [2- (4-chloro-benzenesulfonamido) ethyl] -N-hydroxy-indole-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-Chlor-benzolsulfochlorid und 5-(2-Aminoethyl)-N-hydroxy-indol-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-chloro-benzenesulfonyl chloride and 5- (2-aminoethyl) -N-hydroxy-indole-2-carboxylic acid ethyl ester.

Beispiel 10 aExample 10 a 5-[2-(4-tert-Butyl-benzolsulfonamido)ethyl]benzo[b]-furan-2-carbonsäureethylester5- [2- (4-tert-Butyl-benzenesulfonamido) ethyl] benzo [b] -furan-2-carboxylic acid ethyl ester

In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung aus 4-tert-Butyl-benzolsulfochlorid und 5-(2-Amino-ethyl)benzo[b]-furan-2-carbonsäureethylester.In an analogous manner to that described in Example 1, the title compound is obtained from 4-tert-butyl-benzenesulfonyl chloride and 5- (2-amino-ethyl) benzo [b] -furan-2-carboxylic acid ethyl ester.

Beispiel 11Example 11 5-[2-(4-Chlor benzolsulfonamido)ethyl]benzo[b]furan-2-carbonsäure5- [2- (4-chlorobenzenesulfonamido) ethyl] benzo [b] furan-2-carboxylic acid

Eine Mischung aus 5.0 g (12.2 mmol) Verbindung des Beispiels 1, 25 ml Ethanol und 25 ml 2 N Natronlauge rührt man 1 h bei 50°C, engt ein, wäscht mit Ethylacetat, stellt die wässrige Phase sauer, filtriert und trocknet den Niederschlag im Vakuum. Man isoliert4.3 g derTitelverbindung (93% d.Th.) vom Schmp.193-195°C.A mixture of 5.0 g (12.2 mmol) of the compound of Example 1, 25 ml of ethanol and 25 ml of 2N sodium hydroxide solution is stirred for 1 h at 50 ° C., concentrated, washed with ethyl acetate, the aqueous phase is acidic, filtered and dries the precipitate in vacuo. 4.3 g of the title compound (93% of theory) with a melting point of 193-195 ° C are isolated.

Beispiel 12Example 12

In analoger Weise wie in Beispiel 11 beschrieben erhält man :

Figure imgb0008
Figure imgb0009
 In an analogous manner to that described in Example 11, one obtains:
Figure imgb0008
Figure imgb0009

Beispiel 13Example 13 5-(2-Benzolsulfonamido-ethyl)-2,3-dihydrobenzo[b]furan-2-carbonsäure5- (2-benzenesulfonamido-ethyl) -2,3-dihydrobenzo [b] furan-2-carboxylic acid

Eine Mischung aus 1.2 g Verbindung des Beispiels 2a, 50 ml Ethanol und 0,5 g Palladiumkohle wird 3 Tage unter 280 bar Wasserstoffdruck auf 100°C erhitzt. Man versetzt mit verd. Natronlauge, erwärmt 2h auf 50°C, filtriert, säuert an, filtriert und reinigt den Niederschlag durch Chromatographie.A mixture of 1.2 g of the compound of Example 2a, 50 ml of ethanol and 0.5 g of palladium-carbon is heated to 100 ° C. under a hydrogen pressure of 280 bar for 3 days. Dilute sodium hydroxide solution is added, the mixture is warmed to 50 ° C. for 2 hours, filtered, acidified, filtered and the precipitate is purified by chromatography.

Man isoliert 300 mg (25% d.Th.) titelverbindung, vom Schmp. 132-133°C (aus Ether).300 mg (25% of theory) of the title compound are isolated, with a melting point of 132-133 ° C. (from ether).

Beispiel 14Example 14 5-[2-(4-Chlor-benzolsulfonamido)ethyl)indol-2-carbonsäureethylester5- [2- (4-Chloro-benzenesulfonamido) ethyl) indole-2-carboxylic acid ethyl ester

Die Verbindung des Beispiels 9 kann auch auf folgendem Wege erhalten werden :The compound of Example 9 can also be obtained in the following way:

a) 4-[2-(4-Chlor-benzolsulfonamido)ethyl]nitrobenzola) 4- [2- (4-Chloro-benzenesulfonamido) ethyl] nitrobenzene

Zu einer Mischung aus 9.0 g (44 mmol) 4-Nitrophenethylaminohydrochlorid (Chem. Ber. 45, 2431 (1921), 100 ml Dichlormethan und 13.5 g Triethylamin tropft man unter Eiskühlung die Lösung von 9.8 g (44 mmol) 4-Chlorbenzolsulfochlorid in 50 ml Dichlormethan. Man rührt 1 h nach, gießt auf Eis, extrahiert mit Dichlormethan, trocknet und engt ein. Es verbleiben 14.0 g Titelverbindung (89% d.Th.) vom Schmp. 151-152°C (aus Ethanol).The solution of 9.8 g (44 mmol) of 4-chlorobenzenesulfonyl chloride in 50 is added dropwise to a mixture of 9.0 g (44 mmol) of 4-nitrophenethylaminohydrochloride (Chem. Ber. 45, 2431 (1921), 100 ml of dichloromethane and 13.5 g of triethylamine while cooling with ice ml of dichloromethane, the mixture is stirred for 1 h, poured onto ice, extracted with dichloromethane, dried and concentrated, leaving 14.0 g of the title compound (89% of theory) with a melting point of 151-152 ° C. (from ethanol).

b) 4-[2-(4-Chlor-benzolsulfonamido)ethyl]anilin-hydrochloridb) 4- [2- (4-chloro-benzenesulfonamido) ethyl] aniline hydrochloride

11.5 g (34 mmol) der vorstehenden Nitroverbindung werden in 1 Liter Methanol über 0.5 g sulfidiertem Platinkatalysator hydrisiert. Nach Aufnahme der berechneten Wasserstoffmenge wird filtriert und mit etherischer Chlorwasserstofflösung versetzt. Man erhält 10.5 g Titelverbindung (quantitativ) vom Schmp. 228-230°C.11.5 g (34 mmol) of the above nitro compound are hydrogenated in 1 liter of methanol over 0.5 g of sulfided platinum catalyst. After the calculated amount of hydrogen has been taken up, the mixture is filtered and an ethereal hydrogen chloride solution is added. 10.5 g of the title compound (quantitative) of mp 228-230 ° C.

c) Brenztraubensäure-4-[2-(4-chlorbenzolsulfonamidorethyl]phenyl-hydrazonc) Pyruvic acid 4- [2- (4-chlorobenzenesulfonamidorethyl] phenyl hydrazone

Eine Mischung aus 8.9 g (26 mmol) des vorstehenden Hydrochlorids, 300 ml Wasser und 14 ml konz. Salzsäure wird bei Raumtemp. mit einer Lösung aus 1.8 g Natriumnitrat in 20 ml Wasser versetzt.A mixture of 8.9 g (26 mmol) of the above hydrochloride, 300 ml of water and 14 ml of conc. Hydrochloric acid is at room temp. mixed with a solution of 1.8 g sodium nitrate in 20 ml water.

Zu einer Mischung aus 3.9 g (26 mmol) 2-Methylacetessigester und 100 g Eiswasser tropft man gleichzeitig die vorstehende Diazoninusalzlösung sowie eine Lösung von 14 g Kaliumhydroxid in 40 ml Wasser. Man rührt 15 min nach, stellt mit Salzsäure sauer, extrahiert mit Ether, trocknet und engt ein.The above diazonium salt solution and a solution of 14 g of potassium hydroxide in 40 ml of water are simultaneously added dropwise to a mixture of 3.9 g (26 mmol) of 2-methyl acetoacetate and 100 g of ice water. The mixture is stirred for 15 min, acidified with hydrochloric acid, extracted with ether, dried and concentrated.

Es verbleiben 13.0 g (91% d.Th.) eines roten Öls, das roh weiterverarbeitet wird.There remain 13.0 g (91% of theory) of a red oil, which is further processed raw.

d) 5-[2-(4-Chlor-benzolsulfonamido)ethyl]indol-2-carbonsäureethylesterd) 5- [2- (4-chloro-benzenesulfonamido) ethyl] indole-2-carboxylic acid ethyl ester

Eine Mischung aus 1.0 g (2.4 mmol) des vorstehenden Öls, 9 ml Eisessig und 1 ml konz. Schwefelsäure wird 5 min zum Sieden erhitzt. Man gießt auf Eis, extrahiert mit Essigester, wäscht neutral, trocknet und engt ein. Nach Umkristallisation aus Ethanol erhält man 300 mg (31% d.Th.) Titelverbindung vom Schmp. 192-195°C.A mixture of 1.0 g (2.4 mmol) of the above oil, 9 ml of glacial acetic acid and 1 ml of conc. Sulfuric acid is heated to boiling for 5 min. It is poured onto ice, extracted with ethyl acetate, washed neutral, dried and concentrated. After recrystallization from ethanol, 300 mg (31% of theory) of the title compound, mp. 192-195 ° C.

1. Sulfonamide der allgemeinen Formel I1. Sulfonamides of the general formula I

Claims (6)

1. Sulphonamides of the general formula I
Figure imgb0017
in which R1 and R2 can be the same or different and each signifies hydrogen, a halogen atom, a C1 to Ce- alkyl, C1 to C6-alkoxy, C1 to C6-alkylthio, C1 to C6-alkylsulphinyl, C1 to C6-alkylsulphonyl, trifluoromethyl, hydroxyl or cyano group, R3 and R8 can be the same or different and each signifies hydrogen, a C1 to Ce-alkyl, a benzyl or a C1 to C6-alkanoyl group, R4 and R5 can be the same or different and each signifies hydrogen or a C1 to C6-alkyl group, Re and R7 each represent hydrogen atoms or together form a valency bond, X stands for oxygen, sulphur, a group NOH or a group NR8 and n signifies a whole number from 1 to 4 ; their physiologically acceptable salts of inorganic or organic bases.
2. Sulphonamides of the formula I according to claim 1, in which R1' R3 and R8 signify hydrogen, R2 hydrogen, bromine, chlorine, methyl or methoxy, R4 hydrogen or methyl, R5 hydrogen or ethyl, R6 and R7 together form a valency bond, X stands for oxygen, sulphur atom or a group NR8, n signifies a whole number 1 or 2 and the sulphonamido radical stands in the 5-position of the heterocycle.
3. Process for the preparation of sulphonamides of the formula I
Figure imgb0018
in which R1 and R2 can be the same or different and each signifies hydrogen, a halogen atom, a C1 to Ce- alkyl, C1 to C6-alkoxy, C1 to C6-alkylthio, C1 to C6-alkylsulphinyl, C1 to C6-alkylsulphonyl, trifluoromethyl, hydroxyl or cyano groups, R3 and R8 can be the same or different and each signifies hydrogen, a C1 to C6-alkyl, a benzyl or a C1 to C6-alkanoyl group, R4 and R5 can be the same or different and each signifies hydrogen or a C1 to Ce6alkyl group, R6 and R7 each represent hydrogen or together form a valency bond, X stands for oxygen, sulphur, a group NOH or a group NR8 and n signifies a whole number from 1 to 4, of the physiologically acceptable salts of inorganic or organic bases, characterised in that, in per se known manner, one either
a) reacts a compound of the general formula ll
Figure imgb0019
in which R1 and R2 have the above-given meanings, or a reactive derivative thereof with a compound of the general formula lll
Figure imgb0020
in which R3, R4, R5, R6, R7 X and _n have the abovegiven meanings, or
b) reacts a compound of the general formula IV
Figure imgb0021
in which R1' R2 and R3 have the above-given meanings, with a compound of the general formula V
Figure imgb0022
in which R4,-R5, R6, R7, X and n have the above-given meanings and Y represents a reactive residue, or
c) for the case that X represents the group NH and R6 and R7 together form a valency bond, reduces a compound of the general formula VI
Figure imgb0023
in which R1, R2, R3 and n have the above-given meanings, according to a combined Japp-Klingemann/Fischer indole synthesis, converts the resultant amino group in the usual way into a diazonium group, reacts the diazonium group with 2-methylacetoacetic acid ester and cyclises the resultant hydrazone to the indole, and subsequently, if desired, converts a radical R3, R5 or R8 into another radical R3, R5 or R8 given by the definition in question, removes a valency bond formed by R6 and R7 together by hydrogenolysis, converts an alkylthio group standing for R1 or R2 into an alkylsulphinyl group or alkylsulphonyl group by oxidation, converts an alkoxy radical standing for R1 or R2 into a hydroxyl group or a hydroxyl group into an alkoxy radical and, if desired, converts the compounds obtained of the formula I into their physiologically acceptable salts by neutralisation with non-toxic bases.
4. Medicaments containing a compound according to claim 1 or 2, as well as usual carrier and adjuvant materials.
5. Use of compounds according to claim 1 or 2 for the preparation of medicaments for the treatment of metabolic diseases.
6. Use of compounds according to claim 1 or 2 for the preparation of medicaments for the treatment of circulatory disturbances.
EP88121188A 1987-12-24 1988-12-17 Heterocyclically substituted alkyl sulfone amides, method for their preparation, and pharmaceutical preparations Expired - Lifetime EP0322692B1 (en)

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